8a,14-dihydroxy-7,8-dihydrocodeinone

ABSTRACT

8α,14-Dihydroxy-7,8-dihydrocodeinone is described.

This application is a divisional of U.S. patent application Ser. No.11/729,741, filed Mar. 29, 2007, which is a continuation of U.S. patentapplication Ser. No. 11/391,897, filed Mar. 29, 2006, which is acontinuation of U.S. patent application Ser. No. 11/093,626, filed Mar.30, 2005, now U.S. Pat. No. 7,129,248, which claims priority to U.S.Provisional Application No. 60/651,778, filed Feb. 10, 2005, U.S.Provisional Application No. 60/648,625, filed Jan. 31, 2005, U.S.Provisional Application No. 60/620,072, filed Oct. 18, 2004, U.S.Provisional Application No. 60/601,534, filed Aug. 13, 2004, and U.S.Provisional Application No. 60/557,492, filed Mar. 30, 2004, all ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a process for reducing the amount of14-hydroxycodeinone in an oxycodone hydrochloride preparation.

BACKGROUND OF THE INVENTION

Oxycodone is a semi-synthetic opioid analgesic that exerts an agonisteffect at specific, saturable opioid receptors in the CNS and othertissues. In man, oxycodone may produce any of a variety of effectsincluding analgesia.

Purdue Pharma L.P currently sells sustained-release oxycodone in dosageforms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under thetrade name OxyContin®.

U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912; and 5,656,295 disclosesustained release oxycodone formulations.

Thebaine, a compound derived from opium, although having no medicinaluse in itself, is useful as a starting material in synthetic schemes forthe production of oxycodone. In other schemes, codeine can be utilizedas the starting material for the production of oxycodone.14-hydroxycodeinone is the immediate precursor to oxycodone in theseschemes.

Methods of producing thebaine or 14-hydroxy substituted opiumderivatives have been reported, e.g. in U.S. Pat. No. 3,894,026 and U.S.Pat. No. 4,045,440.

The oxidation of codeine to codeinone, an initial step in the synthesisof opium derivatives has been reported in EP 0889045, U.S. Pat. No.6,008,355 and in the J. Am. Chem. Soc., 1051, 73, 4001 (Findlay).

The reaction of codeinone to 14-hydroxycodeinone has been reported inU.S. Pat. No. 6,008,355 and in Tetrahedron 55, 1999 (Coop and Rice).

The methylation of codeinone to thebaine has been reported inHeterocycles, 1988, 49, 43-7 (Rice) and EP0889045.

U.S. Pat. No. 6,177,567 describes the hydrogenation of14-hydroxycodeinone to oxycodone by reduction with diphenylsilane andPd(Ph3P)/ZnCl2 or with sodium hypophosphite in conjunction with a Pd/Ccatalyst in aqueous acetic acid.

Krabnig et al. in “Optimization of the Synthesis of Oxycodone and5-Methyloxycodone” Arch. Pharm. (1996), 329(6), (325-326) describeshydrogenating a solution of 14-hydroxycodeinone in glacial acetic acidwith a Pd—C-catalyst at 30 psi at the described conditions.

During the oxidation of thebaine to give 14-hydroxycodeinone, severaloveroxidized products are formed including8,14-dihydroxy-7,8-dihydrocodeinone. In the production of oxycodone freebase from the 14-hydroxycodeinone, the8,14-dihydroxy-7,8-dihydrocodeinone is carried though the process.During conversion of the oxycodone free base to oxycodone hydrochloride,the impurity undergoes acid-catalyzed dehydration and is converted into14-hydroxycodeinone. Thus, 14-hydroxycodeinone is present in the finaloxycodone hydrochloride composition. Oxycodone hydrochloride API (activepharmaceutical ingredient) is available from a variety of manufacturerssuch as Johnson Matthey and Mallinckrodt. Current commercially-availableoxycodone hydrochloride API, and oxycodone hydrochloride prepared byknown procedures, have a level of 14-hydroxycodeinone of greater than100 ppm.

There is a continuing need in the art to provide an oxycodonehydrochloride composition that contains reduced amounts of14-hydroxycodeinone as compared to compositions known in the art.

All references cited herein are incorporated by reference in theirentireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a process for reducing the 14-hydroxycodeinone in an oxycodonehydrochloride composition to an amount of less than 25 ppm, less thanabout 15 ppm, less than about 10 ppm, or less than about 5 ppm.

It is an object of certain embodiments of the present invention toprovide a process for reacting an oxycodone base composition withhydrochloric acid under conditions to produce an oxycodone hydrochloridecomposition having an amount of 14-hydroxycodeinone of less than 25 ppm,less than about 15 ppm, less than about 10 ppm, or less than about 5ppm.

It is a further object of certain embodiments of the present inventionto provide an oxycodone hydrochloride composition having a14-hydroxycodeinone level of less than 25 ppm, less than about 15 ppm,less than about 10 ppm, or less than about 5 ppm.

It is a further object of certain embodiments of the present inventionto provide a process for preparing an oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level of less than 25 ppm byreacting an oxycodone base composition with hydrochloric acid underconditions suitable to promote dehydration of8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone during saltformation and under reducing conditions so as to convert the14-hydroxycodeinone to oxycodone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level of less than 25 ppm comprising reacting anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelof more than 100 ppm under conditions that reduce the amount of14-hydroxycodeinone to a level of less than 25 ppm, less than about 15ppm, less than about 10 ppm, or less than about 5 ppm.

In certain embodiments, the invention is directed town oxycodonehydrochloride composition having a 14-hydroxycodeinone level of lessthan 25 ppm, less than about 15 ppm, less than about 10 ppm, or lessthan about 5 ppm.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level of less than 25 ppm comprising subjecting anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelof greater than 100 ppm to hydrogenation to an extent that the amount of14-hydroxycodeinone in the composition is reduced to an amount of lessthan less 25 ppm, less than about 15 ppm, less than about 10 ppm, orless than about 5 ppm.

In certain embodiments disclosed herein, the oxycodone compositionhaving a 14-hydroxycodeinone level of less than 25 ppm can besubsequently hydrogenated to further decrease the amount of14-hydroxycodeinone, e.g., from about 15 ppm to about 10 ppm or less.

In one embodiment, where the starting material is an oxycodonehydrochloride composition comprising 14-hydroxycodeinone in an amount of100 ppm or higher, the final oxycodone hydrochloride composition has a14-hydroxycodeinone level of less than 25 ppm, less than about 15 ppm,less than about 10 ppm, or less than about 5 ppm. In another embodiment,where the starting material is an oxycodone hydrochloride compositioncomprising 14-hydroxycodeinone in an amount of between 15 ppm and 25ppm, the final oxycodone hydrochloride composition has a14-hydroxycodeinone level of less than about 10 ppm, or less than about5 ppm. In another embodiment, where the starting material is anoxycodone hydrochloride composition comprising 14-hydroxycodeinone in anamount of between 10 ppm and 25 ppm, the final oxycodone hydrochloridecomposition has a 14-hydroxycodeinone level of less than about 5 ppm.

In certain embodiments of the present invention, the process forpreparing the oxycodone hydrochloride composition having a14-hydroxycodeinone level of less than 25 ppm comprises hydrogenatingthe starting material under reflux. In certain embodiments, the processfurther comprises recovering the resultant oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level of less than 25 ppm.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level of less than 25 ppm comprising hydrogenatingunder reflux, a starting oxycodone hydrochloride composition having a14-hydroxycodeinone level of greater than 100 ppm in a suitable solventfor a time sufficient, to produce an oxycodone composition having a14-hydroxycodeinone level of less than 25 ppm, less than about 15 ppm,less than about 10 ppm, or less than about 5 ppm; and recovering theoxycodone hydrochloride composition having a 14-hydroxycodeinone levelof less than 25 ppm by crystallization and removal from the solvent(e.g., by filtration).

In certain embodiments, the oxycodone hydrochloride composition of thepresent invention has a lower limit of 0.25 ppm, 0.5 ppm, 1 ppm, 2 ppmor 5 ppm of 14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingreacting in a suitable solvent an oxycodone base composition withhydrochloric acid in an amount greater than 1.0 molar equivalent ascompared to the oxycodone base composition, the reacting step beingperformed under reducing conditions, to form an oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level in an amount of less than25 ppm.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone comprising hydrogenating a 14-hydroxycodeinonecomposition to obtain an oxycodone free base composition; converting theoxycodone free base composition to oxycodone hydrochloride; andhydrogenating the oxycodone hydrochloride to obtain an oxycodonecomposition having less than 25 ppm 14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone comprising hydrogenating a 14-hydroxycodeinonecomposition to obtain an oxycodone free base composition; converting theoxycodone free base composition to oxycodone hydrochloride; isolatingthe oxycodone hydrochloride; and hydrogenating the oxycodonehydrochloride to obtain an oxycodone composition having less than 25 ppm14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone comprising oxidizing a thebaine composition to form14-hydroxycodeinone composition, the oxidizing being performed at asuitable pH to minimize or eliminate the production of8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinonecomposition; hydrogenating the 14-hydroxycodeinone composition to forman oxycodone base composition; and converting the oxycodone basecomposition to an oxycodone hydrochloride composition having less than25 ppm 14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing 14-hydroxycodeinone comprising oxidizing a thebainecomposition to form 14-hydroxycodeinone composition, the oxidizing beingperformed at a suitable pH to minimize or eliminate the production of8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinonecomposition;

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition comprising reacting anoxycodone base composition with an acid having a higher pH thanhydrochloric acid to form a corresponding acid addition salt ofoxycodone, and converting the acid addition salt of oxycodone tooxycodone hydrochloride.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingcontacting an oxycodone base composition having an amount of8,14-dihydroxy-7,8-dihydrocodeinone with a substance that preferentiallyremoves the 8,14-dihydroxy-7,8-dihydrocodeinone as compared to theoxycodone base; and converting the oxycodone base composition to anoxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingsubjecting an oxycodone base composition having an amount of8,14-dihydroxy-7,8-dihydrocodeinone to chromatographic separation topreferentially removes the 8,14-dihydroxy-7,8-dihydrocodeinone ascompared to the oxycodone base; and converting the oxycodone basecomposition to an oxycodone hydrochloride composition having less than25 ppm 14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingreacting in a suitable solvent an oxycodone base composition having anamount of 8,14-dihydroxy-7,8-dihydrocodeinone, with boronatedpolystyrene resin; and converting the oxycodone base composition to anoxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition comprising reacting ina suitable solvent an oxycodone base composition with boronatedpolystyrene resin; and converting the oxycodone base composition to anoxycodone hydrochloride composition.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingcombining hydrochloric acid and an oxycodone base composition having anamount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form asolution; and spray drying the solution to generate oxycodonehydrochloride composition having a 14-hydroxycodeinone level in anamount of less than 25 ppm.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition having a14-hydroxycodeinone level in an amount of less than 25 ppm comprisingcombining hydrochloric acid and an oxycodone base composition having anamount of 8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form asolution; and lyophilizing the solution to generate oxycodonehydrochloride composition having a 14-hydroxycodeinone level in anamount of less than 25 ppm.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition comprising combininghydrochloric acid and an oxycodone base composition in a solvent to forma solution; and spray drying the solution to generate oxycodonehydrochloride.

In certain embodiments, the invention is directed to a process forpreparing an oxycodone hydrochloride composition comprising combininghydrochloric acid and an oxycodone base composition in a solvent to forma solution; and lyophilizing the solution to generate oxycodonehydrochloride. The term “bulk” means an amount of material of at least 1kg. In certain embodiments, the amount can be from about 10 kg to about1000 kg or from about 10 kg to about 500 kg. In certain embodiments, theamount is in an amount of from about 20 kg to about 100 kg; about 20 kgor about 50 kg. Bulk oxycodone hydrochloride composition can bepackaged, e.g., in a pharmaceutically acceptable package such ascorrugated box containers (made of, e.g., plastic and/or paper); indrums (made of, e.g., a metal or metal composite material); or in bagsof woven fabric generally referred to as flexible intermediate bulkcontainers (FIBCs). Each of these approaches use various configurationsof liners, typically made of polyethylene or polypropylene, that fitwithin the corrugated box, drum, or within the FIBC for preventingcontamination of the product being shipped. Preferably, these packagingapproaches use containers configured to be supported by and carried onpallets.

The term “ppm” as used herein means “parts per million”. As used torefer to 14-hydroxycodeinone, “ppm” means parts per million of14-hydroxycodeinone in a particular sample.

The term 8,14-dihydroxy-7,8-dihydrocodeinone includes either8α,14-dihydroxy-7,8-dihydrocodeinone; or88,14-dihydroxy-7,8-dihydrocodeinone or can include a mixture of bothcompounds.

The oxycodone hydrochloride preparation can be, e.g., an oxycodoneactive pharmaceutical ingredient (API), such as oxycodone hydrochlorideU.S.P., uncombined or combined with one or more other ingredients. Forexample, the oxycodone preparation can be a final pharmaceutical dosageform, or an intermediate preparation for a final dosage form, that canbe tested for the presence of 14-hydroxycodeinone and/or codeinone,e.g., for quality assurance purposes. Preferably, the oxycodonehydrochloride preparation is oxycodone hydrochloride API and contains atleast 95% oxycodone hydrochloride, at least 98% oxycodone hydrochloride,at least 99% oxycodone hydrochloride, or at least 99.9% oxycodonehydrochloride.

The method of detecting the presence of 14-hydroxycodeinone in anoxycodone preparation can be performed in accordance with commonlyassigned U.S. Provisional Application Ser. No. 60/557,502, entitled“Methods For Detecting 14-Hydroxycodeinone” filed Mar. 29, 2004 and inaccordance with U.S. Provisional Application entitled “Methods ForDetecting 14-Hydroxycodeinone” filed Jan. 31, 2005.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a reaction of thebaine to oxycodonehydrochloride, including the oxidation of thebaine to14-hydroxycodeinone and the 8,14-dihydroxy-7,8-dihydrocodeinoneimpurity.

FIG. 2 is a schematic of the dehydration of8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone.

FIG. 3 depicts a separation of the system suitability testing solutionof Example 4.

FIG. 4 depicts a HPLC chromatogram for the Working 100 PPM 14OHCStandard Solution of Example 4.

FIG. 5 depicts typical HPLC cluomatogram for the Oxycodone API SampleSolution of Example 4.

DETAILED DESCRIPTION

In certain embodiments, the invention is directed to a process forreducing the amount of 14-hydroxycodeinone in an oxycodone hydrochloridecomposition (e.g., oxycodone hydrochloride API), and to the resultantoxycodone hydrochloride composition having a 14-hydroxycodeinone levelof less than 25 ppm recovered from that process. In certain embodiments,the present invention is directed to a process for reducing the amountof 14-hydroxycodeinone in an oxycodone hydrochloride compositioncomprising reacting the oxycodone hydrochloride composition with acatalytically effective amount of a transition metal compound and a gascomprising hydrogen, at a temperature and for a period of timesufficient to reduce the content of 14-hydroxycodeinone to a levelwherein the resultant oxycodone hydrochloride composition comprises14-hydroxycodeinone in an amount less than 25 ppm, less than about 15ppm; less than about 10 ppm, or less than about 5 ppm.

The process of the present invention also may result in the reduction ofother alpha, beta, unsaturated ketones in oxycodone compositions, inaddition to 14-hydroxycodeinone such as, e.g., codeinone.

In accordance with certain embodiments of the present invention, anoxycodone hydrochloride composition (e.g., oxycodone hydrochloride API),and a solvent, are fed into a reaction apparatus. The composition isthen hydrogenated under adequate conditions for a sufficient period; thecatalyst is removed from the solvent; and the oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level of less than 25 ppm isisolated and removed, e.g., by crystallization and filtration.

Hydrogenation of the 14-hydroxycodeinone in the processes of the presentinvention can be accomplished by using, e.g., pressurized-catalytichydrogenation or catalytic transfer hydrogenation in an appropriateacid, e.g., acetic acid. A particular hydrogenation reaction employshydrogen gas or NaHPO₂ along with a palladium-carbon catalyst. Incertain embodiments, a hydrogen donor for use in the hydrogenation ofthe 14-hydroxycodeinone can be selected from hydrogen, primary andsecondary alcohols, primary and secondary amines, carboxylic acids andtheir esters and amine salts, readily dehydrogenatable hydrocarbons(e.g., lower alkyl-substituted aromatic hydrocarbons such asethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene,o-ethyltoluene, m-ethyltoluene, p-ethyltoluene, o-isopropyltoluene,m-isopropyltoluene, p-isopropyltoluene, ethylnaphthalene,propylnapththalene, isopropylnaphthalene, and diethylnaphthalene;paraffins such as ethane, propane, n-butane, isobutane, n-pentane,isopentane, n-hexane, n-heptane, n-octane, n-nonane, n-decane, andbranched chain isomers thereof; cycloparaffins such as cyclobutane,cyclopentane, cyclohexane, methylcyclopentane, methylcyclohexane, andethylcyclopentane; olefins such as ethylene, propylene, 1-butene,2-butene, 1-pentene, 2-pentene, 1-hexene, 2-hexene, 3-hexene, andbranched chain derivatives thereof), clean reducing agents (e.g.,polymer-supported organotin hydrides, and any suitable combinationthereof. In certain embodiments, the hydrogenation can be performed asdisclosed in U.S. Provisional Application No. 60/477,968, filed Jun. 12,2003, entitled “Hydrogenation of Opioids Without Hydrogen Gas Feed.”

In certain embodiments, the hydrogenation is carried out at a pressurefrom about 5 PSIG to about 200 PSIG, or from about 40 PSIG to about 60PSIG. In certain embodiments, the hydrogenation is carried out at atemperature of from about 20° C. to about 100° C., or from about 40° C.to about 85° C.

In certain embodiments, the hydrogenation is carried out at a pH of lessthan 5, less than 3, or less than 1, e.g., about 0.5.

In certain embodiments of the present invention, the 14-hydroxycodeinoneis converted to oxycodone by hydrogenation utilizing diphenylsilane andPd(Ph₃P)/ZnCl₂ and sodium hypophosphite in conjunction with a Pd/Ccatalyst in aqueous organic acid; or Pd/C catalytic transferhydrogenation.

The total reaction time of the hydrogenation reaction is for a durationsufficient to reduce the content of the 14-hydroxycodeinone to a levelthat is less than 25 ppm, less than about 15 ppm, less than about 10ppm, or less than about 5 ppm. The actual reaction time can varydepending upon the temperature and efficiency of the hydrogenationsystem. Depending on the hydrogenation conditions (e.g., temperature andpressure), the total reaction time to achieve the desired reduction in14-hydroxycodeinone can be, e.g., from about 10 minutes to about 36hours. The hydrogenation of the 14-hydroxycodeinone can be carried outin the presence of a noble metal catalyst. In certain embodiments,suitable catalysts can be selected from Raney cobalt, Raney nickel,palladium on carbon, platinum on carbon, palladium on alumina, platinumoxide, ruthenium on alumina, rhodium on alumina, or rhodium on carbon,among others. One particular catalyst for this reduction is 5% palladiumon carbon. The quantity of palladium on carbon catalyst can be fromabout 0.05% w/w to about 50% w/w, or from about 0.5% w/w to about 5%, inrelation to the treated composition.

The reaction may be carried out in a solvent such as water; an alcohol(such as, e.g., isopropanol, methanol or ethanol); tetrahydrofuran; anaromatic hydrocarbon (such as benzene); an ether (such as dioxane); anester of a lower alkanoic acid (such as methyl acetate or ethylacetate); an amide (such as, e.g., dimethylformamide, diethylformamide,dimethylacetomide, or other N-alkyl substituted lower fatty acidamides); N-methylpyrrolidone; formylmorpholine; β-methoxypropionitrile;a carboxylic acid (such as formic, acetic, propionic acid or other loweralkanoic acid) or an appropriate mixture of any two or more of theaforementioned solvents. One particular co-solvent combination isisopropanol/water.

In certain embodiments, the solvent is typically mixed with the14-hydroxycodeinone-containing composition (e.g., an oxycodonecomposition) prior to hydrogenation.

In certain embodiments, the invention is directed to the conversion ofan oxycodone free base composition (with an8,14-dihydroxy-7,8-dihydrocodeinone component) to oxycodonehydrochloride. During salt formation reactions known in the art, the8,14-dihydroxy-7,8-dihydrocodeinone component is converted to14-hydroxycodeinone by acid-catalyzed dehydration. Thus,14-hydroxycodeinone is increased in the final product. By virtue of thepresent invention, this can be reduced by overloading the amount ofhydrochloric acid in the salt formation to promote the reaction of8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone and providingreducing conditions sufficient for the 14-hydroxycodeinone to be readilyconverted to oxycodone. In such an embodiment, the amount ofhydrochloric acid is an amount of greater than 1 molar equivalent ascompared to the oxycodone free base. In certain embodiments, the molarequivalent amount of hydrochloric acid can be greater than about 1.2molar equivalents or greater than about 1.4 molar equivalents. Incertain embodiments, the amount of hydrochloric acid can be about 1.5molar equivalents. The reducing conditions sufficient to drive the14-hydroxycodeinone to oxycodone can be provided, e.g., by a catalystwith a hydrogen donor.

Further, during salt formation, the rate of dehydration of8,14-dihydroxy-7,8-dihydrocodeinone to 14-hydroxycodeinone is reduced asthe pH of the solution increases. Therefore, in certain embodiments, thepH of the solution can be adjusted to a pH of from about 1.5 to about2.5, preferably to about 1.8, (e.g., from a pH of less than 1) with asuitable basic agent, e.g., sodium hydroxide. This further minimizes theformation of 14-hydroxycodeinone from8,14-dihydroxy-7,8-dihydrocodeinone during crystallization. Preferably,the pH adjustment is performed after the hydrogenation step and prior toremoval of catalyst and isolation of the oxycodone having a14-hydroxycodeinone level of less than 25 ppm.

In certain embodiments it may be necessary to perform the process of thepresent invention, or one or more relevant steps in the process of thepresent invention, more than once in order to reduce the amount of14-hydroxycodeinone to a desired level, e.g., less than about 10 ppm, orless than about 5 ppm.

In certain embodiments of the present invention, oxycodone hydrochloridecompositions can be prepared by certain alternative processes. Suchalternative processes preferably result in an oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level in an amount of less than25 ppm. One such alternative process is directed to a process forpreparing an oxycodone hydrochloride composition having less than 25 ppm14-hydroxycodeinone comprising oxidizing a thebaine composition to form14-hydroxycodeinone composition, the oxidizing being performed at asuitable pH to minimize or eliminate the production of8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinonecomposition; hydrogenating the 14-hydroxycodeinone composition to forman oxycodone base composition; and converting the oxycodone basecomposition to an oxycodone hydrochloride composition having less than25 ppm 14-hydroxycodeinone.

Another alternative process is directed to a process for preparing14-hydroxycodeinone comprising oxidizing a thebaine composition to forma 14-hydroxycodeinone composition, the oxidizing being performed at asuitable pH to minimize or eliminate the production of8,14-dihydroxy-7,8-dihydrocodeinone in the 14-hydroxycodeinonecomposition.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition comprising reacting an oxycodonebase composition with an acid having a higher pH than hydrochloric acidto form a corresponding acid addition salt of oxycodone, and convertingthe acid addition salt of oxycodone to oxycodone hydrochloride. In suchan embodiment, the acid may be selected from the group consisting oftartaric acid, oxalic acid, fumaric acid, phosphoric acid, sulfuric acidand mixtures thereof.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising contacting an oxycodone basecomposition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone witha substance that preferentially removes the8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base;and converting the oxycodone base composition to an oxycodonehydrochloride composition having less than 25 ppm 14-hydroxycodeinone.In preferred embodiments the contacting substance can be a gel. Infurther embodiments, the contacting can comprise passing a solutioncomprising the oxycodone base composition through the substance or cancomprise forming a slurry with the oxycodone base composition and thegel.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising subjecting an oxycodone basecomposition having an amount of 8,14-dihydroxy-7,8-dihydrocodeinone tochromatographic separation to preferentially remove the8,14-dihydroxy-7,8-dihydrocodeinone as compared to the oxycodone base;and converting the oxycodone base composition to an oxycodonehydrochloride composition having less than 25 ppm 14-hydroxycodeinone.In preferred embodiments, the chromatographic separation is a simulatedmoving bed.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising contacting an oxycodonehydrochloride composition having an amount of 14-hydroxycodeinone with asubstance that preferentially removes the 14-hydroxycodeinone ascompared to the oxycodone hydrochloride; and recovering an oxycodonehydrochloride composition having less than 25 ppm 14-hydroxycodeinone.In preferred embodiments the contacting substance can be a gel. Infurther embodiments, the contacting can comprise passing a solutioncomprising the oxycodone hydrochloride composition through the substanceor can comprise forming a slurry with the oxycodone hydrochloridecomposition and the gel.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising subjecting an oxycodonehydrochloride composition having an amount of 14-hydroxycodeinone tochromatographic separation to preferentially remove the14-hydroxycodeinone as compared to the oxycodone hydrochloride; andrecovering an oxycodone hydrochloride composition having less than 25ppm 14-hydroxycodeinone. In preferred embodiments, the chromatographicseparation is a simulated moving bed.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising reacting in a suitablesolvent an oxycodone base composition having an amount of8,14-dihydroxy-7,8-dihydrocodeinone, with boronated polystyrene resin;and converting the oxycodone base composition to an oxycodonehydrochloride composition having less than 25 ppm 14-hydroxycodeinone.Preferably the reacting is performed at a temperature below about 20degrees C.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition comprising reacting in a suitablesolvent an oxycodone base composition with boronated polystyrene resin;and converting the oxycodone base composition to an oxycodonehydrochloride composition. Preferably the reacting is performed at atemperature below about 20 degrees C.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising combining hydrochloric acidand an oxycodone base composition having an amount of8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; andspray drying the solution to generate oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level in an amount of less than25 ppm.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition having a 14-hydroxycodeinone levelin an amount of less than 25 ppm comprising combining hydrochloric acidand an oxycodone base composition having an amount of8,14-dihydroxy-7,8-dihydrocodeinone in a solvent to form a solution; andlyophilizing the solution to generate oxycodone hydrochloridecomposition having a 14-hydroxycodeinone level in an amount of less than25 ppm.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition comprising combining hydrochloricacid and an oxycodone base composition in a solvent to form a solution;and spray drying the solution to generate oxycodone hydrochloride.

Another alternative process is directed to a process for preparing anoxycodone hydrochloride composition comprising combining hydrochloricacid and an oxycodone base composition in a solvent to form a solution;and lyophilizing the solution to generate oxycodone hydrochloride.

Further Embodiments

The oxycodone hydrochloride having a 14-hydroxycodeinone level of lessthan 25 ppm can be incorporated into pharmaceutical dosage forms, e.g.,by admixtures of the oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm with conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances. For oral formulations, the dosage forms can providea sustained release of the active. Suitable pharmaceutically acceptablecarriers include but are not limited to, alcohols, gum arabic, vegetableoils, benzyl alcohols, polyethylene glycols, gelate, carbohydrates suchas lactose, amylose or starch, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,disintegrants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure buffers, coloring, flavoringand/or aromatic substances and the like. The compositions intended fororal use may be prepared according to any method known in the art andsuch compositions may contain one or more agents selected from the groupconsisting of inert, non-toxic pharmaceutically acceptable excipientswhich are suitable for the manufacture of tablets. Such excipientsinclude, for example an inert diluent such as lactose; granulating anddisintegrating agents such as cornstarch; binding agents such as starch;and lubricating agents such as magnesium stearate. The tablets may beuncoated or they may be coated by known techniques for elegance or todelay release of the active ingredients. Formulations for oral use mayalso be presented as hard gelatin capsules wherein the active ingredientis mixed with an inert diluent. The oral dosage forms of the presentinvention may be in the form of tablets (sustained release and/orimmediate release), troches, lozenges, powders or granules, hard or softcapsules, microparticles (e.g., microcapsules, microspheres and thelike), buccal tablets, suppositories, solutions, suspensions, etc.

In certain embodiments, the present invention provides for a method oftreating pain by administering to a human patient the dosage formsdescribed herein.

When the dosage form is oral, the dosage form of the present inventioncontains from about 10 mg to about 320 mg of oxycodone hydrochloridehaving a 14-hydroxycodeinone level of less than 25 ppm. Particularlypreferred dosages for twice daily dosing are about 5 mg, about 10 mg,about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about60 mg, about 80 mg, about 100 mg, or about 160 mg. Particularlypreferred dosages for once daily dosing are about 10 mg, about 20 mg,about 30 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about120 mg, about 160 mg, or about 320 mg. The oxycodone hydrochloridehaving a 14-hydroxycodeinone level of less than 25 ppm can also beformulated with suitable pharmaceutically acceptable excipients toprovide a sustained release of the oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm. Such formulations can beprepared in accordance with U.S. Pat. Nos. 5,266,331; 5,508,042;5,549,912; and 5,656,295.

The oxycodone hydrochloride having a 14-hydroxycodeinone level of lessthan 25 ppm can be formulated as a sustained release oral formulation inany suitable tablet, coated tablet or multiparticulate formulation knownto those skilled in the art. The sustained release dosage form mayinclude a sustained release material which is incorporated into a matrixalong with the oxycodone or salt thereof.

The sustained release dosage form may optionally comprise particlescontaining oxycodone having a 14-hydroxycodeinone level of less than 25ppm. In certain embodiments, the particles have a diameter from about0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.Preferably, the particles are film coated with a material that permitsrelease of the active at a sustained rate in an aqueous medium. The filmcoat is chosen so as to achieve, in combination with the other statedproperties, desired release properties. The sustained release coatingformulations of the present invention should preferably be capable ofproducing a strong, continuous film that is smooth and elegant, capableof supporting pigments and other coating additives, non-toxic, inert,and tack-free.

Coated Beads

In certain embodiments of the present invention a hydrophobic materialis used to coat inert pharmaceutical beads such as nu pariel 18/20beads, and a plurality of the resultant solid sustained release beadsmay thereafter be placed in a gelatin capsule in an amount sufficient toprovide an effective sustained release dose when ingested and contactedby an environmental fluid, e.g., gastric fluid or dissolution media.

The sustained release bead formulations of the present invention slowlyrelease the active of the present invention, e.g., when ingested andexposed to gastric fluids, and then to intestinal fluids. The sustainedrelease profile of the formulations of the invention can be altered, forexample, by varying the amount of overcoating with the hydrophobicmaterial, altering the manner in which a plasticizer is added to thehydrophobic material, by varying the amount of plasticizer relative tohydrophobic material, by the inclusion of additional ingredients orexcipients, by altering the method of manufacture, etc. The dissolutionprofile of the ultimate product may also be modified, for example, byincreasing or decreasing the thickness of the retardant coating.

Spheroids or beads coated with the agent(s) of the present are prepared,e.g., by dissolving the agent(s) in water and then spraying the solutiononto a substrate, for example, nu pariel 18/20 beads, using a Wusterinsert. Optionally, additional ingredients are also added prior tocoating the beads in order to assist the binding of the active to thebeads, and/or to color the solution, etc. For example, a product whichincludes hydroxypropylmethylcellulose, etc. with or without colorant(e.g., Opadry®, commercially available from Colorcon, Inc.) may be addedto the solution and the solution mixed (e.g., for about 1 hour) prior toapplication of the same onto the beads. The resultant coated substrate,in this example beads, may then be optionally overcoated with a barrieragent, to separate the active(s) from the hydrophobic sustained releasecoating. An example of a suitable barrier agent is one which compriseshydroxypropylmethylcellulose. However, any film-former known in the artmay be used. It is preferred that the barrier agent does not affect thedissolution rate of the final product.

The beads may then be overcoated with an aqueous dispersion of thehydrophobic material. The aqueous dispersion of hydrophobic materialpreferably further includes an effective amount of plasticizer, e.g.triethyl citrate. Pre-formulated aqueous dispersions of ethylcellulose,such as Aquacoat® or Surelease®, may be used. If Surelease® is used, itis not necessary to separately add a plasticizer. Alternatively,pre-formulated aqueous dispersions of acrylic polymers such as Eudragit®can be used.

The coating solutions of the present invention preferably contain, inaddition to the film-former, plasticizer, and solvent system (i.e.,water), a colorant to provide elegance and product distinction. Colormay be added to the solution of the therapeutically active agentinstead, or in addition to the aqueous dispersion of hydrophobicmaterial. For example, color may be added to Aquacoat® via the use ofalcohol or propylene glycol based color dispersions, milled aluminumlakes and opacifiers such as titanium dioxide by adding color with shearto water soluble polymer solution and then using low shear to theplasticized Aquacoat®. Alternatively, any suitable method of providingcolor to the formulations of the present invention may be used. Suitableingredients for providing color to the formulation when an aqueousdispersion of an acrylic polymer is used include titanium dioxide andcolor pigments, such as iron oxide pigments. The incorporation ofpigments, may, however, increase the retard effect of the coating.

Plasticized hydrophobic material may be applied onto the substratecomprising the agent(s) by spraying using any suitable spray equipmentknown in the art. In a preferred method, a Wurster fluidized-bed systemis used in which an air jet, injected from underneath, fluidizes thecore material and effects drying while the acrylic polymer coating issprayed on. A sufficient amount of the hydrophobic material to obtain apredetermined sustained release of the agent(s) when the coatedsubstrate is exposed to aqueous solutions, e.g. gastric fluid, may beapplied. After coating with the hydrophobic material, a further overcoatof a film-former, such as Opadry®, is optionally applied to the beads.This overcoat is provided, if at all, in order to substantially reduceagglomeration of the beads.

The release of the agent(s) from the sustained release formulation ofthe present invention can be further influenced, i.e., adjusted to adesired rate, by the addition of one or more release-modifying agents,or by providing one or more passageways through the coating. The ratioof hydrophobic material to water soluble material is determined by,among other factors, the release rate required and the solubilitycharacteristics of the materials selected.

The release-modifying agents which function as pore-formers may beorganic or inorganic, and include materials that can be dissolved,extracted or leached from the coating in an environment of use. Thepore-formers may comprise one or more hydrophilic materials such ashydroxypropylmethylcellulose.

The sustained release coatings of the present invention can also includeerosion-promoting agents such as starch and gums.

The sustained release coatings of the present invention can also includematerials useful for making microporous lamina in the environment ofuse, such as polycarbonates comprised of linear polyesters of carbonicacid in which carbonate groups reoccur in the polymer chain.

The release-modifying agent may also comprise a semi-permeable polymer.

In certain preferred embodiments, the release-modifying agent isselected from hydroxypropylmethylcellulose, lactose, metal stearates,and mixtures of any of the foregoing.

The sustained release coatings of the present invention may also includean exit means comprising at least one passageway, orifice, or the like.The passageway may be formed by such methods as those disclosed in U.S.Pat. Nos. 3,845,770; 3,916,8989; 4,063,064; and 4,088,864.

Matrix Formulations

In other embodiments of the present invention, the sustained releaseformulation is achieved via a matrix optionally having a sustainedrelease coating as set forth herein. The materials suitable forinclusion in a sustained release matrix may depend on the method used toform the matrix.

For example, a matrix in addition to the oxycodone hydrochloride havinga 14-hydroxycodeinone level of less than 25 ppm may include:

Hydrophilic and/or hydrophobic materials, such as gums, celluloseethers, acrylic resins, protein derived materials; the list is not meantto be exclusive, and any pharmaceutically acceptable hydrophobicmaterial or hydrophilic material which is capable of imparting sustainedrelease of the agent(s) and which melts (or softens to the extentnecessary to be extruded) may be used in accordance with the presentinvention.

Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀), substituted orunsubstituted hydrocarbons, such as fatty acids, fatty alcohols,glyceryl esters of fatty acids, mineral and vegetable oils and waxes,and stearyl alcohol; and polyalkylene glycols.

Of these polymers, acrylic polymers, especially Eudragit® RSPO—thecellulose ethers, especially hydroxyalkylcelluloses andcarboxyalkylcelluloses, are preferred. The oral dosage form may containbetween 1% and 80% (by weight) of at least one hydrophilic orhydrophobic material.

When the hydrophobic material is a hydrocarbon, the hydrocarbonpreferably has a melting point of between 25° and 90° C. Of the longchain hydrocarbon materials, fatty (aliphatic) alcohols are preferred.The oral dosage form may contain up to 60% (by weight) of at least onedigestible, long chain hydrocarbon.

Preferably, the oral dosage form contains up to 60% (by weight) of atleast one polyalkylene glycol.

The hydrophobic material is preferably selected from the groupconsisting of alkylcelluloses, acrylic and methacrylic acid polymers andcopolymers, shellac, zein, hydrogenated castor oil, hydrogenatedvegetable oil, or mixtures thereof. In certain preferred embodiments ofthe present invention, the hydrophobic material is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate, methylmethacrylate copolymers, ethoxyethyl methacrylates, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid) (anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In other embodiments, the hydrophobicmaterial is selected from materials such as hydroxyalkylcelluloses suchas hydroxypropylmethylcellulose and mixtures of the foregoing.

Preferred hydrophobic materials are water-insoluble with more or lesspronounced hydrophilic and/or hydrophobic trends. Preferably, thehydrophobic materials useful in the invention have a melting point fromabout 2530° to about 200° C., preferably from about 45° C. to about 90°C. Specifically, the hydrophobic material may comprise natural orsynthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl,cetyl or preferably cetostearyl alcohol), fatty acids, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di-, andtri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearicaid, stearyl alcohol and hydrophobic and hydrophilic materials havinghydrocarbon backbones. Suitable waxes include, for example, beeswax,glycowax, castor wax and carnauba wax. For purposes of the presentinvention, a wax-like substance is defined as any material which isnormally solid at room temperature and has a melting point of from about25° to about 100° C.

Suitable hydrophobic materials which may be used in accordance with thepresent invention include digestible, long chain (C₈-C₅₀, especiallyC₁₂-C₄₀), substituted or unsubstituted hydrocarbons, such as fattyacids, fatty alcohols, glyceryl esters of fatty acids, mineral andvegetable oils and natural and synthetic waxes. Hydrocarbons having amelting point of between 25° and 90° C. are preferred. Of the long chainhydrocarbon materials, fatty (aliphatic) alcohols are preferred incertain embodiments. The oral dosage form may contain up to 60% (byweight) of at least one digestible, long chain hydrocarbon.

Preferably, a combination of two or more hydrophobic materials areincluded in the matrix formulations. If an additional hydrophobicmaterial is included, it is preferably selected from natural andsynthetic waxes, fatty acids, fatty alcohols, and mixtures of the same.Examples include beeswax, carnauba wax, stearic acid and stearylalcohol. This list is not meant to be exclusive.

One particular suitable matrix comprises at least one water solublehydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferably C₁₄-C₂₂,aliphatic alcohol and, optionally, at least one polyalkylene glycol. Theat least one hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose,hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose. Theamount of the at least one hydroxyalkyl cellulose in the present oraldosage form will be determined, inter alia, by the precise rate ofoxycodone hydrochloride release required. The at least one aliphaticalcohol may be, for example, lauryl alcohol, myristyl alcohol or stearylalcohol. In particularly preferred embodiments of the present oraldosage form, however, the at least one aliphatic alcohol is cetylalcohol or cetostearyl alcohol. The amount of the at least one aliphaticalcohol in the present oral dosage form will be determined, as above, bythe precise rate of opioidoxycodone release required. It will alsodepend on whether at least one polyalkylene glycol is present in orabsent from the oral dosage form. In the absence of at least onepolyalkylene glycol, the oral dosage form preferably contains between20% and 50% (by wt) of the at least one aliphatic alcohol. When at leastone polyalkylene glycol is present in the oral dosage form, then thecombined weight of the at least one aliphatic alcohol and the at leastone polyalkylene glycol preferably constitutes between 20% and 50% (bywt) of the total dosage.

In one embodiment, the ratio of, e.g., the at least one hydroxyalkylcellulose or acrylic resin to the at least one aliphaticalcohol/polyalkylene glycol determines, to a (w/w) of the at least onehydroxyalkyl cellulose to the at least one aliphaticalcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with aratio of between 1:3 and 1:4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropyleneglycol or, which is preferred, polyethylene glycol. The number averagemolecular weight of the at least one polyalkylene glycol is preferredbetween 1,000 and 15,000 especially between 1,500 and 12,000.

Another suitable sustained release matrix would comprise analkylcellulose (especially ethyl cellulose), a C₁₂ to C₃₆ aliphaticalcohol and, optionally, a polyalkylene glycol.

In another preferred embodiment, the matrix includes a pharmaceuticallyacceptable combination of at least two hydrophobic materials.

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g. diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art.

Matrix—Particulates

In order to facilitate the preparation of a solid, sustained release,oral dosage form according to this invention, any method of preparing amatrix formulation known to those skilled in the art may be used. Forexample incorporation in the matrix may be effected, for example, by (a)forming granules comprising at least one water soluble hydroxyalkylcellulose, and the oxycodone hydrochloride having a 14-hydroxycodeinonelevel of less than 25 ppm; (b) mixing the hydroxyalkyl cellulosecontaining granules with at least one C₁₂-C₃₆ aliphatic alcohol; and (c)optionally, compressing and shaping the granules. Preferably, thegranules are formed by wet granulating the hydroxalkyl cellulosegranules with water.

In yet other alternative embodiments, a spheronizing agent, togetherwith the active can be spheronized to form spheroids. Microcrystallinecellulose is a preferred spheronizing agent. A suitable microcrystallinecellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Corporation). In such embodiments, in addition to the activeingredient and spheronizing agent, the spheroids may also contain abinder. Suitable binders, such as low viscosity, water soluble polymers,will be well known to those skilled in the pharmaceutical art. However,water soluble hydroxy lower alkyl cellulose, such ashydroxypropylcellulose, are preferred. Additionally (or alternatively)the spheroids may contain a water insoluble polymer, especially anacrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethylacrylate copolymer, or ethyl cellulose. In such embodiments, thesustained release coating will generally include a hydrophobic materialsuch as (a) a wax, either alone or in admixture with a fatty alcohol; or(b) shellac or zein.

Melt Extrusion Matrix

Sustained release matrices can also be prepared via melt-granulation ormelt-extrusion techniques. Generally, melt-granulation techniquesinvolve melting a normally solid hydrophobic material, e.g. a wax, andincorporating a powdered drug therein. To obtain a sustained releasedosage form, it may be necessary to incorporate an additionalhydrophobic substance, e.g. ethylcellulose or a water-insoluble acrylicpolymer, into the molten wax hydrophobic material. Examples of sustainedrelease formulations prepared via melt-granulation techniques are foundin U.S. Pat. No. 4,861,598.

The additional hydrophobic material may comprise one or morewater-insoluble wax-like thermoplastic substances possibly mixed withone or more wax-like thermoplastic substances being less hydrophobicthan said one or more water-insoluble wax-like substances. In order toachieve constant release, the individual wax-like substances in theformulation should be substantially non-degradable and insoluble ingastrointestinal fluids during the initial release phases. Usefulwater-insoluble wax-like substances may be those with a water-solubilitythat is lower than about 1:5,000 (w/w).

In addition to the above ingredients, a sustained release matrix mayalso contain suitable quantities of other materials, e.g., diluents,lubricants, binders, granulating aids, colorants, flavorants andglidants that are conventional in the pharmaceutical art. The quantitiesof these additional materials will be sufficient to provide the desiredeffect to the desired formulation.

In addition to the above ingredients, a sustained release matrixincorporating melt-extruded multiparticulates may also contain suitablequantities of other materials, e.g. diluents, lubricants, binders,granulating aids, colorants, flavorants and glidants that areconventional in the pharmaceutical art in amounts up to about 50% byweight of the particulate if desired.

Specific examples of pharmaceutically acceptable carriers and excipientsthat may be used to formulate oral dosage forms are described in theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (1986).

Melt Extrusion Multiparticulates

The preparation of a suitable melt-extruded matrix according to thepresent invention may, for example, include the steps of blending theoxycodone hydrochloride having a 14-hydroxycodeinone level of less than25 ppm together with at least one hydrophobic material and preferablythe additional hydrophobic material to obtain a homogeneous mixture. Thehomogeneous mixture is then heated to a temperature sufficient to atleast soften the mixture sufficiently to extrude the same. The resultinghomogeneous mixture is then extruded to form strands. The extrudate ispreferably cooled and cut into multiparticulates by any means known inthe art. The strands are cooled and cut into multiparticulates. Themultiparticulates are then divided into unit doses. The extrudatepreferably has a diameter of from about 0.1 to about 5 mm and providessustained release of the therapeutically active agent for a time periodof from about 8 to about 24 hours.

An optional process for preparing the melt extrusions of the presentinvention includes directly metering into an extruder a hydrophobicmaterial, the oxycodone hydrochloride having a 14-hydroxycodeinone levelof less than 25 ppm, and an optional binder; heating the homogenousmixture; extruding the homogenous mixture to thereby form strands;cooling the strands containing the homogeneous mixture; cutting thestrands into particles having a size from about 0.1 mm to about 12 mm;and dividing said particles into unit doses. In this aspect of theinvention, a relatively continuous manufacturing procedure is realized.

The diameter of the extruder aperture or exit port can also be adjustedto vary the thickness of the extruded strands. Furthermore, the exitpart of the extruder need not be round; it can be oblong, rectangular,etc. The exiting strands can be reduced to particles using a hot wirecutter, guillotine, etc.

The melt extruded multiparticulate system can be, for example, in theform of granules, spheroids or pellets depending upon the extruder exitorifice. For purposes of the present invention, the terms “melt-extrudedmultiparticulate(s)” and “melt-extruded multiparticulate system(s)” and“melt-extruded particles” shall refer to a plurality of units,preferably within a range of similar size and/or shape and containingone or more active agents and one or more excipients, preferablyincluding a hydrophobic material as described herein. In this regard,the melt-extruded multiparticulates will be of a range of from about 0.1to about 12 mm in length and have a diameter of from about 0.1 to about5 mm. In addition, it is to be understood that the melt-extrudedmultiparticulates can be any geometrical shape within this size range.Alternatively, the extrudate may simply be cut into desired lengths anddivided into unit doses of the therapeutically active agent without theneed of a spheronization step.

In one preferred embodiment, oral dosage forms are prepared to includean effective amount of melt-extruded multiparticulates within a capsule.For example, a plurality of the melt-extruded multiparticulates may beplaced in a gelatin capsule in an amount sufficient to provide aneffective sustained release dose when ingested and contacted by gastricfluid.

In another preferred embodiment, a suitable amount of themultiparticulate extrudate is compressed into an oral tablet usingconventional tableting equipment using standard techniques. Techniquesand compositions for making tablets (compressed and molded), capsules(hard and soft gelatin) and pills are also described in Remington'sPharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980).

In yet another preferred embodiment, the extrudate can be shaped intotablets as set forth in U.S. Pat. No. 4,957,681 (Klimesch, et. al.),described in additional detail above.

Optionally, the sustained release melt-extruded multiparticulate systemsor tablets can be coated, or the gelatin capsule containing themultiparticulates can be further coated, with a sustained releasecoating such as the sustained release coatings described above. Suchcoatings preferably include a sufficient amount of hydrophobic materialto obtain a weight gain level from about 2 to about 30 percent, althoughthe overcoat may be greater depending upon the desired release rate,among other things.

The melt-extruded unit dosage forms of the present invention may furtherinclude combinations of melt-extruded particles before beingencapsulated. Furthermore, the unit dosage forms can also include anamount of an immediate release agent for prompt release. The immediaterelease agent may be incorporated, e.g., as separate pellets within agelatin capsule, or may be coated on the surface of themultiparticulates after preparation of the dosage forms (e.g., sustainedrelease coating or matrix-based). The unit dosage forms of the presentinvention may also contain a combination of sustained release beads andmatrix multiparticulates to achieve a desired effect.

The sustained release formulations of the present invention preferablyslowly release the agent(s), e.g., when ingested and exposed to gastricfluids, and then to intestinal fluids. The sustained release profile ofthe melt-extruded formulations of the invention can be altered, forexample, by varying the amount of retardant, i.e., hydrophobic material,by varying the amount of plasticizer relative to hydrophobic material,by the inclusion of additional ingredients or excipients, by alteringthe method of manufacture, etc.

In other embodiments of the invention, the melt extruded material isprepared without the inclusion of the oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm, which can be addedthereafter to the extrudate. Such formulations typically will have theagents blended together with the extruded matrix material, and then themixture would be tableted in order to provide a slow releaseformulation.

Coatings

The dosage forms of the present invention may optionally be coated withone or more materials suitable for the regulation of release or for theprotection of the formulation. In one embodiment, coatings are providedto permit either pH-dependent or pH-independent release. A pH-dependentcoating serves to release the active in desired areas of thegastro-intestinal (GI) tract, e.g., the stomach or small intestine, suchthat an absorption profile is provided which is capable of providing atleast about eight hours and preferably about twelve hours to up to abouttwenty-four hours of analgesia to a patient. When a pH-independentcoating is desired, the coating is designed to achieve optimal releaseregardless of pH-changes in the environmental fluid, e.g., the GI tract.It is also possible to formulate compositions which release a portion ofthe dose in one desired area of the GI tract, e.g., the stomach, andrelease the remainder of the dose in another area of the GI tract, e.g.,the small intestine.

Formulations according to the invention that utilize pH-dependentcoatings to obtain formulations may also impart a repeat-action effectwhereby unprotected drug is coated over the enteric coat and is releasedin the stomach, while the remainder, being protected by the entericcoating, is released further down the gastrointestinal tract. Coatingswhich are pH-dependent may be used in accordance with the presentinvention include shellac, cellulose acetate phthalate (CAP), polyvinylacetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, andmethacrylic acid ester copolymers, zein, and the like.

In certain preferred embodiments, the substrate (e.g., tablet core bead,matrix particle) containing the oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm thereof is coated with ahydrophobic material selected from (i) an alkylcellulose; (ii) anacrylic polymer; or (iii) mixtures thereof. The coating may be appliedin the form of an organic or aqueous solution or dispersion. The coatingmay be applied to obtain a weight gain from about 2 to about 25% of thesubstrate in order to obtain a desired sustained release profile.Coatings derived from aqueous dispersions are described, e.g., in detailin U.S. Pat. Nos. 5,273,760 and 5,286,493.

Other examples of sustained release formulations and coatings which maybe used in accordance with the present invention include those describedin U.S. Pat. Nos. 5,324,351; 5,356,467, and 5,472,712.

Alkylcellulose Polymers

Cellulosic materials and polymers, including alkylcelluloses, providehydrophobic materials well suited for coating the beads according to theinvention. Simply by way of example, one preferred alkylcellulosicpolymer is ethylcellulose, although the artisan will appreciate thatother cellulose and/or alkylcellulose polymers may be readily employed,singly or in any combination, as all or part of a hydrophobic coatingaccording to the invention.

Acrylic Polymers

In other preferred embodiments of the present invention, the hydrophobicmaterial comprising the sustained release coating is a pharmaceuticallyacceptable acrylic polymer, including but not limited to acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamide copolymer,poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate)copolymer, polyacrylamide, aminoalkyl methacrylate copolymer,poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.

In certain preferred embodiments, the acrylic polymer is comprised ofone or more ammonio methacrylate copolymers. Ammonio methacrylatecopolymers are well known in the art, and are described in NF XVII asfully polymerized copolymers of acrylic and methacrylic acid esters witha low content of quaternary ammonium groups.

In order to obtain a desirable dissolution profile, it may be necessaryto incorporate two or more ammonio methacrylate copolymers havingdiffering physical properties, such as different molar ratios of thequaternary ammonium groups to the neutral (meth)acrylic esters.

Certain methacrylic acid ester-type polymers are useful for preparingpH-dependent coatings which may be used in accordance with the presentinvention. For example, there are a family of copolymers synthesizedfrom diethylaminoethyl methacrylate and other neutral methacrylicesters, also known as methacrylic acid copolymer or polymericmethacrylates, commercially available as Eudragit® from Röhm Tech, Inc.There are several different types of Eudragit®. For example, Eudragit® Eis an example of a methacrylic acid copolymer which swells and dissolvesin acidic media. Eudragit® L is a methacrylic acid copolymer which doesnot swell at about pH<5.7 and is soluble at about pH>6. Eudragit® S doesnot swell at about pH<6.5 and is soluble at about pH>7. Eudragit® RL andEudragit® RS are water swellable, and the amount of water absorbed bythese polymers is pH-dependent, however, dosage forms coated withEudragit® RL and RS are pH-independent.

In certain preferred embodiments, the acrylic coating comprises amixture of two acrylic resin lacquers commercially available from RohmPharma under the Tradenames Eudragit® RL30D and Eudragit® RS30D,respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers ofacrylic and methacrylic esters with a low content of quaternary ammoniumgroups, the molar ratio of ammonium groups to the remaining neutral(meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit®RS30D. The mean molecular weight is about 150,000. The code designationsRL (high permeability) and RS (low permeability) refer to thepermeability properties of these agents. Eudragit® RL/RS mixtures areinsoluble in water and in digestive fluids. However, coatings formedfrom the same are swellable and permeable in aqueous solutions anddigestive fluids.

The Eudragit® RL/RS dispersions of the present invention may be mixedtogether in any desired ratio in order to ultimately obtain a sustainedrelease formulation having a desirable dissolution profile. Desirablesustained release formulations may be obtained, for instance, from aretardant coating derived from 100% Eudragit® RL, 50% Eudragit® RL and50% Eudragit® RS, and 10% Eudragit® RL: Eudragit® 90% RS. Of course, oneskilled in the art will recognize that other acrylic polymers may alsobe used, such as, for example, Eudragit® L.

Plasticizers

In embodiments of the present invention where the coating comprises anaqueous dispersion of a hydrophobic material, the inclusion of aneffective amount of a plasticizer in the aqueous dispersion ofhydrophobic material will further improve the physical properties of thesustained release coating. For example, because ethyl-cellulose has arelatively high glass transition temperature and does not form flexiblefilms under normal coating conditions, it is preferable to incorporate aplasticizer into an ethylcellulose coating containing sustained releasecoating before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the film-former, e.g., most often from about 1 to about50 percent by weight of the film-former. Concentration of theplasticizer, however, can only be properly determined after carefulexperimentation with the particular coating solution and method ofapplication.

Examples of suitable plasticizers for ethylcellulose include waterinsoluble plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, and triacetin, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) may be used.Triethyl citrate is an especially preferred plasticizer for the aqueousdispersions of ethyl cellulose of the present invention.

Examples of suitable plasticizers for the acrylic polymers of thepresent invention include, but are not limited to citric acid esterssuch as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate,and possibly 1,2-propylene glycol. Other plasticizers which have provedto be suitable for enhancing the elasticity of the films formed fromacrylic films such as Eudragit® RL/RS lacquer solutions includepolyethylene glycols, propylene glycol, diethyl phthalate, castor oil,and triacetin. Triethyl citrate is an especially preferred plasticizerfor the aqueous dispersions of ethyl cellulose of the present invention.

It has further been found that the addition of a small amount of talcreduces the tendency of the aqueous dispersion to stick duringprocessing, and acts as a polishing agent.

Sustained Release Osmotic Dosage Form

Sustained release dosage forms according to the present invention mayalso be prepared as osmotic dosage formulations. The osmotic dosageforms preferably include a bilayer core comprising a drug layer(containing the oxycodone hydrochloride having a 14-hydroxycodeinonelevel of less than 25 ppm) and a delivery or push layer, wherein thebilayer core is surrounded by a semipermeable wall and optionally havingat least one passageway disposed therein.

The expression “passageway” as used for the purpose of this invention,includes aperture, orifice, bore, pore, porous element through whichoxycodone hydrochloride having a 14-hydroxycodeinone level of less than25 ppm can be pumped, diffuse or migrate through a fiber, capillarytube, porous overlay, porous insert, microporous member, or porouscomposition. The passageway can also include a compound that erodes oris leached from the wall in the fluid environment of use to produce atleast one passageway. Representative compounds for forming a passagewayinclude erodible poly(glycolic) acid, or poly(lactic) acid in the wall;a gelatinous filament; a water-removable poly(vinyl alcohol); leachablecompounds such as fluid-removable pore-forming polysaccharides, acids,salts or oxides. A passageway can be formed by leaching a compound fromthe wall, such as sorbitol, sucrose, lactose, maltose, or fructose, toform a sustained-release dimensional pore-passageway. The dosage formcan be manufactured with one or more passageways in spaced-apartrelation on one or more surfaces of the dosage form. A passageway andequipment for forming a passageway are disclosed in U.S. Pat. Nos.3,845,770; 3,916,899; 4,063,064 and 4,088,864. Passageways comprisingsustained-release dimensions sized, shaped and adapted as areleasing-pore formed by aqueous leaching to provide a releasing-pore ofa sustained-release rate are disclosed in U.S. Pat. Nos. 4,200,098 and4,285,987.

In certain embodiments the drug layer may also comprise at least onepolymer hydrogel. The polymer hydrogel may have an average molecularweight of between about 500 and about 6,000,000. Examples of polymerhydrogels include but are not limited to a maltodextrin polymercomprising the formula (C₆H₁₂O₅)_(n).H₂O, wherein n is 3 to 7,500, andthe maltodextrin polymer comprises a 500 to 1,250,000 number-averagemolecular weight; a poly(alkylene oxide) represented by, e.g., apoly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to750,000 weight-average molecular weight, and more specificallyrepresented by a polyethylene oxide) of at least one of 100,000,200,000, 300,000 or 400,000 weight-average molecular weights; an alkalicarboxyalkylcellulose, wherein the alkali is sodium or potassium, thealkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000weight-average molecular weight; and a copolymer of ethylene-acrylicacid, including methacrylic and ethacrylic acid of 10,000 to 500,000number-average molecular weight.

In certain embodiments of the present invention, the delivery or pushlayer comprises an osmopolymer. Examples of an osmopolymer include butare not limited to a member selected from the group consisting of apolyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxidepossesses a 1,000,000 to 10,000,000 weight-average molecular weight. Thepolyalkylene oxide may be a member selected from the group consisting ofpolymethylene oxide, polyethylene oxide, polypropylene oxide,polyethylene oxide having a 1,000,000 average molecular weight,polyethylene oxide comprising a 5,000,000 average molecular weight,polyethylene oxide comprising a 7,000,000 average molecular weight,cross-linked polymethylene oxide possessing a 1,000,000 averagemolecular weight, and polypropylene oxide of 1,200,000 average molecularweight. Typical osmopolymer carboxyalkylcellulose comprises a memberselected from the group consisting of alkali carboxyalkylcellulose,sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodiumcarboxyethylcellulose, lithium carboxymethylcellulose, sodiumcarboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcelluloseand carboxymethylhydroxypropylcellulose. The osmopolymers used for thedisplacement layer exhibit an osmotic pressure gradient across thesemipermeable wall. The osmopolymers imbibe fluid into dosage form,thereby swelling and expanding as an osmotic hydrogel (also known asosmogel), whereby they push the oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm thereof from the osmoticdosage form.

The push layer may also include one or more osmotically effectivecompounds also known as osmagents and as osmotically effective solutes.They imbibe an environmental fluid, for example, from thegastrointestinal tract, into dosage form and contribute to the deliverykinetics of the displacement layer. Examples of osmotically activecompounds comprise a member selected from the group consisting ofosmotic salts and osmotic carbohydrates. Examples of specific osmagentsinclude but are not limited to sodium chloride, potassium chloride,magnesium sulfate, lithium phosphate, lithium chloride, sodiumphosphate, potassium sulfate, sodium sulfate, potassium phosphate,glucose, fructose and maltose.

The push layer may optionally include a hydroxypropylalkylcellulosepossessing a 9,000 to 450,000 number-average molecular weight. Thehydroxypropylethylcellulose is represented by a member selected from thegroup consisting of hydroxypropylmethylcellulose,hydroxypropylethylcellulose, hydroxypropyl isopropyl cellulose,hydroxypropylbutylcellulose, and hydroxypropylpentylcellulose.

The push layer optionally may comprise a nontoxic colorant or dye.Examples of colorants or dyes include but are not limited to Food andDrug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&CNo. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide,carbon black, and indigo.

The push layer may also optionally comprise an antioxidant to inhibitthe oxidation of ingredients. Some examples of antioxidants include butare not limited to a member selected from the group consisting ofascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixtureof 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene,sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodiumbisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, andpropylgallate.

In certain alternative embodiments, the dosage form comprises ahomogenous core comprising oxycodone hydrochloride having a14-hydroxycodeinone level of less than 25 ppm, a pharmaceuticallyacceptable polymer (e.g., polyethylene oxide), Optionally a disintegrant(e.g., polyvinylpyrrolidone), optionally an absorption enhancer (e.g., afatty acid, a surfactant, a chelating agent, a bile salt, etc.). Thehomogenous core is surrounded by a semipermeable wall having apassageway (as defined above) for the release of the oxycodonehydrochloride having a 14-hydroxycodeinone level of less than 25 ppm.

In certain embodiments, the semipermeable wall comprises a memberselected from the group consisting of a cellulose ester polymer, acellulose ether polymer and a cellulose ester-ether polymer.Representative wall polymers comprise a member selected from the groupconsisting of cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulose diacetate,mono-, di- and tricellulose alkenylates, and mono-, di- and tricellulosealkinylates. The poly(cellulose) used for the present inventioncomprises a number-average molecular weight of 20,000 to 7,500,000.

Additional semipermeable polymers for the purpose of this inventioncomprise acetaldehyde dimethycellulose acetate, cellulose acetateethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate,propylcarbamate, cellulose acetate diethylaminoacetate; semipermeablepolyamide; semipermeable polyurethane; semipermeable sulfonatedpolystyrene; semipermeable cross-linked polymer formed by thecoprecipitation of a polyanion and a polycation as disclosed in U.S.Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876;semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat.No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeablecross-linked poly(sodium styrene sulfonate); semipermeable crosslinkedpoly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymerspossessing a fluid permeability of 2.5×10⁻⁸ to 2.5×10⁻² (cm²/hr·atm)expressed per atmosphere of hydrostatic or osmotic pressure differenceacross the semipermeable wall. Other polymers useful in the presentinvention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.J. Roff, 1971, CRC Press, Cleveland, Ohio.

In certain embodiments, preferably the semipermeable wall is nontoxic,inert, and it maintains its physical and chemical integrity during thedispensing life of the drug. In certain embodiments, the dosage formcomprises a binder. An example of a binder includes, but is not limitedto a therapeutically acceptable vinyl polymer having a 5,000 to 350,000viscosity-average molecular weight, represented by a member selectedfrom the group consisting of poly-n-vinylamide, poly-n-vinylacetamide,poly(vinyl pyrrolidone), also known as poly-n-vinylpyrrolidone,poly-n-vinylcaprolactone, poly-n-vinyl-5-methyl-2-pyrrolidone, andpoly-n-vinyl-pyrrolidone copolymers with a member selected from thegroup consisting of vinyl acetate, vinyl alcohol, vinyl chloride, vinylfluoride, vinyl butyrate, vinyl laureate, and vinyl stearate. Otherbinders include for example, acacia, starch, gelatin, andhydroxypropylalkylcellulose of 9,200 to 250,000 average molecularweight.

In certain embodiments, the dosage form comprises a lubricant, which maybe used during the manufacture of the dosage form to prevent sticking todie wall or punch faces. Examples of lubricants include but are notlimited to magnesium stearate, sodium stearate, stearic acid, calciumstearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid,sodium stearyl fumarate, and magnesium palmitate.

In certain preferred embodiments, the present invention includes atherapeutic composition comprising an amount of oxycodone hydrochloridehaving a 14-hydroxycodeinone level of less than 25 ppm equivalent to 10to 40 mg oxycodone hydrochloride, 25 to 500 mg of poly(alkylene oxide)having a 150,000 to 500,000 average molecular weight, 1 to 50 mg ofpolyvinylpyrrolidone having a 40,000 average molecular weight, and 0 toabout 7.5 mg of a lubricant.

Suppositories

The sustained release formulations of the present invention may beformulated as a pharmaceutical suppository for rectal administrationcomprising a suitable suppository base, and oxycodone hydrochloridehaving a 14-hydroxycodeinone level of less than 25 ppm. Preparation ofsustained release suppository formulations is described in, e.g., U.S.Pat. No. 5,215,758.

Prior to absorption, the drug must be in solution. In the case ofsuppositories, solution must be preceded by dissolution of thesuppository base, or the melting of the base and subsequent partition ofthe drug from the suppository base into the rectal fluid. The absorptionof the drug into the body may be altered by the suppository base. Thus,the particular suppository base to be used in conjunction with aparticular drug must be chosen giving consideration to the physicalproperties of the drug. For example, lipid-soluble drugs will notpartition readily into the rectal fluid, but drugs that are onlyslightly soluble in the lipid base will partition readily into therectal fluid.

Among the different factors affecting the dissolution time (or releaserate) of the drugs are the surface area of the drug substance presentedto the dissolution solvent medium, the pH of the solution, thesolubility of the substance in the specific solvent medium, and thedriving forces of the saturation concentration of dissolved materials inthe solvent medium. Generally, factors affecting the absorption of drugsfrom suppositories administered rectally include suppository vehicle,absorption site pH, drug pKa, degree of ionization, and lipidsolubility.

The suppository base chosen should be compatible with the active of thepresent invention. Further, the suppository base is preferably non-toxicand nonirritating to mucous membranes, melts or dissolves in rectalfluids, and is stable during storage.

In certain preferred embodiments of the present invention for bothwater-soluble and water-insoluble drugs, the suppository base comprisesa fatty acid wax selected from the group consisting of mono-, di- andtriglycerides of saturated, natural fatty acids of the chain length C₁₂to C₁₈.

In preparing the suppositories of the present invention other excipientsmay be used. For example, a wax may be used to form the proper shape foradministration via the rectal route. This system can also be usedwithout wax, but with the addition of diluent filled in a gelatincapsule for both rectal and oral administration.

Examples of suitable commercially available mono-, di- and triglyceridesinclude saturated natural fatty acids of the 12-18 carbon atom chainsold under the trade name Novata™ (types AB, AB, B, BC, BD, BBC, E, BCF,C, D and 299), manufactured by Henkel, and Witepsol™ (types H5, H12,H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58,E75, E76 and E85), manufactured by Dynamit Nobel.

Other pharmaceutically acceptable suppository bases may be substitutedin whole or in part for the above-mentioned mono-, di- andtriglycerides. The amount of base in the suppository is determined bythe size (i.e. actual weight) of the dosage form, the amount of base(e.g., alginate) and drug used. Generally, the amount of suppositorybase is from about 20 percent to about 90 percent by weight of the totalweight of the suppository. Preferably, the amount of suppository base inthe suppository is from about 65 percent to about 80 percent; by weightof the total weight of the suppository.

Additional Embodiments

The oxycodone hydrochloride having a 14-hydroxycodeinone level of lessthan 25 ppm may be used as a substitute for the oxycodone hydrochloridein any existing commercial product such as, e.g., Tylox®, Roxilox®,Roxicet®, Percocet®, Oxycet®, Percodan®, Roxycodone®, OxyContin® andOxyIR®. Such formulations are listed in the PDR 58th Edition (2004) andthe FDA Orange Book.

The following examples illustrate various aspects of the presentinvention. They are not to be construed to limit the claims in anymanner whatsoever.

Example 1

In Example 1, 37.7 g of oxycodone HCl (35.4 g dry basis, ca. 500 ppm14-hydroxycodeinone) was placed in a 500 mL Parr reaction bottle andcombined with 0.55 g 5% Pd/C catalyst, 50% water wet (Johnson Mattheytype 87L), and 182.2 g of 61.9% isopropanol/water (w/w). The mixture wasplaced under an inert atmosphere and heated with shaking to 45-50° C.Upon dissolution of all starting material, the pressure in the bottlewas vented to the atmosphere and hydrogen pressure was applied (45 PSIG)for 4 hours. At the end of the hydrogenation, the hydrogen was ventedoff and the solution was allowed to cool to room temperature.

The next day, the mixture was heated to 75° C. to dissolve thecrystallized solids and then suction filtered over a 0.2 μm PTFEmembrane into a 1 L jacketed cylindrical flask (equipped with acondenser, a nitrogen atmosphere, a mechanical stirrer, a type Kthermocouple, and a programmable refrigerated recirculator). The Parrbottle was rinsed with deionized water (11.7 g), which was added to the1 L flask through the filter. Isopropanol (334.7 g) was added to theflask and the mixture was re-heated with stirring to 75° C. and held todissolve any crystallized solids. The solution was cooled with stirringto 0-10° C. over 8 hours (linear ramp) and held at 0-10° C. for 20hours. The crystallized solid was then collected by suction filtrationand washed with 107 g of cold 95:5 isopropanol/water (w/w).

To remove isopropanol from product, the solvent-wet material wastransferred to a drying dish and placed in a vacuum desiccator with anopen container of deionized water. The solid was held in this manner,under vacuum, overnight. The material was then dried under vacuum at 60°C.

Analysis of the dried material using the low 14-hydroxycodeinone methodof Example 4 below gave a result of 6 ppm of 14-hydroxycodeinone.

Analysis of the dried material using the method of Example 6 below gavea result of <5 ppm of codeinone and 8 ppm of 14-hydroxycodeinone.

Example 2

In Example 2, 35.0 g of oxycodone HCl (33.3 g dry basis, ca. 4000 ppm14-hydroxycodeinone) was placed in a 500 ml Parr reaction bottle andcombined with 0.49 g 5% Pd/C catalyst, 50% water wet (Johnson Mattheytype 87L), and 159.9 g of 62.3% isopropanol/water. The mixture wasplaced under an inert atmosphere and then heated with shaking to 45-50°C. Upon dissolution of the starting material, the pressure in the bottlewas vented to the atmosphere and hydrogen pressure was applied (45PSIG). After 5.25 hours of shaking, the hydrogen was vented off, and thesolution was allowed to cool to room temperature. The mixture wasre-heated the next day and hydrogenation was continued for 4.75 hours.

The mixture was heated to 75° C. and then suction filtered over a 0.2 μmPTFE membrane into a 1 L jacketed cylindrical flask (equipped with adistillation head, a nitrogen atmosphere, a mechanical stirrer, a type Kthermocouple, and a programmable refrigerated recirculator). The Parrbottle was rinsed with deionized water (11.7 g), which was added to the1 L flask through the filter.

Isopropanol (295.6 g) was added to the flask and the mixture was heatedto boiling (ca. 81° C.). To remove water and increase the yield,isopropanol/water azeotrope was distilled from the flask until 305.7 ghad been collected. Fresh isopropanol (305.6 g) was added and thedistillation head was removed and replaced with a condenser.

The mixture was cooled with stirring from boiling to 0-10° C. over 8hours (linear ramp) and held at 0-10° C. for 20 hours. The crystallizedsolid was then collected by suction filtration and washed with 107 g ofcold 95:5 isopropanol/water. The material was dried as described inExample 1.

Analysis of the dried material using the low 14-hydroxycodeinone methodof Example 4 below gave a result of <5 ppm of 14-hydroxycodeinone.

Analysis of the dried material using the method of Example 6 below gavea result of <5 ppm of codeinone and <5 ppm of 14-hydroxycodeinone.

Example 3

In Example 3, 27.83 g of oxycodone free-base, water wet (24.57 g drybasis, 0.0779 mol, ca. 3000 ppm 14-hydroxycodeinone), 39.8 g ofdeionized water, 81.9 g of isopropanol, 0.49 g 5% Pd/C catalyst, 50%water wet (Johnson Matthey type 87L), and cone. HCl (11.3 g, 0.117 mol,1.50 equivalents based on 37.7% HCl assay) were combined in a 500 mlParr shaker bottle.

The mixture was placed under an inert atmosphere and heated to 75° C.with shaking. The pressure in the bottle was relieved, and the systemwas pressurized with hydrogen (45 PSIG). The solution was held underthese conditions for 21.7 hours. Analysis by HPLC showed that the ratioof the area of the 8,14-dihydroxy-7,8-dihydrocodeinone peak to that ofoxycodone was reduced from 0.29% to 0.04% during this time.

The hydrogen pressure was vented and the system was placed under aninert atmosphere. In order to prevent further dehydration of anyresidual 8,14-dihydroxy-7,8-dihydrocodeinone, the pH of the solution wasadjusted from 0.5 to 1.8 with 20.7 g NaOH saturated isopropanol (somesolid sodium hydroxide was also present).

The solution was re-heated to 75° C. and then pressure filtered througha 0.2 μm PTFE membrane filter housed in heat-traced 47 mm SS filterholder into a 500 ml jacketed cylindrical reactor (condenser, N₂,mechanical stirrer, programmable refrigerated recirculator). The Parrbottle was rinsed with 8.6 g of deionized water, which was added to theflask through the filter.

Isopropanol (222.5 g) was added to the solution in the flask and theresulting slurry was heated to approximately 75° C. to re-dissolve thesolids. After reaching the desired temperature, the solution was heldfor two hours (to simulate typical processing times). No14-hydroxycodeinone was detected in a sample of the crystallizationmixture after this hold.

The circulator was set to cool from 80° C. to 0° C. over 8 hours.Approximately 24 hours after starting the cooling program, the solidswere collected by suction filtration and washed three times with 95:5isopropanol/water (232.8 g total). The material was dried as describedin Example 1.

Analysis of the dried material using the low 14-hydroxycodeinone methodof Example 4 below gave a result of 5 ppm of 14-hydroxycodeinone.

Analysis of the dried material using the method of Example 6 below gavea result of <5 ppm of codeinone and 10 ppm of 14-hydroxycodeinone.

Example 4

Analysis of sample to determine 14-hydroxycodeinone level.

The products of Examples 1-3 were analyzed to determine the level of14-hydroxycodeinone under 100 parts per million (PPM) level by a HPLCmethod using a Waters Atlantis 5 μm dC18, 3×250 mm column maintained at50° C. and isocratic elution using pH 9.35, 17 mM ammonium carbonatebuffer and methanol (60:40). Quantitation was achieved by measuring thepeak area response with UV detection at 220 nm using external standard.This method utilized mobile phase with volatile components that arecompatible with LC/MS analysis.

The reagents used were as follows:

1. Ammonium carbonate, analytical reagent grade (Aldrich);

2. Water, HPLC grade;

3. Methanol, HPLC grade;

4. Acetic acid, reagent grade (J. T Baker Glacial Acetic Acid);

5. Ammonium hydroxide, reagent grade;

6. Phosphoric acid, about 85%, A.C.S. reagent;

7. 14-Hydroxycodeinone reference material from Albany MolecularResearch, Inc.

The equipment used was as follows:

A. HPLC System

1. HPLC system capable of delivering 0.4 mL/minute of mobile phase(Waters Alliance);

2. UV/Visible detector set to monitor the eluant at 220 mu (Waters 2487UV/Vis);

3. Autosampler capable of injecting 6 μL;

4. Integrator or suitable data recording system (Waters Millennium 32chromatograph system);

5. Waters, Atlantis dC18 column, 3×250 mm, 5 μm;

6. Column heater capable of maintaining a constant temperature of 50°C.;

7. On-line vacuum degasser.

B. Equipment for Mobile Phase Preparation

1. pH meter, preferably with automatic temperature compensation (ATC);

2. Ultrasonic bath, Model 5200, Branson;

3. 0.45-μm membrane filters for aqueous solvent, Whatman or Millipore,Cellulose acetate or Nylon.

Solutions

17 mM Ammonium carbonate, pH 9.35

1.6±0.1 g of ammonium carbonate was weighed and placed into a 1-Lbeaker. 1000 mL of water was added to the beaker and stirred with amagnetic stirrer until the ammonium carbonate was dissolved. The pH wasadjusted to 9.35-9.40 with ammonium hydroxide.

B. Mobile Phase

400 mL of HPLC-grade methanol was mixed with 600 mL of 17 mM ammoniumcarbonate, pH 9.35-9.40 prepared above. The mixture was filtered throughsolvent membrane filters and then degassed using an on-line vacuumdegasser in the HPLC system.

C. 0.85% Phosphoric Acid Solution

10.0 mL of 85% H₃PO₄ was pipetted into a 1 liter volumetric flask anddiluted to volume with water and mixed thoroughly.

D. 14-Hydroxycodeinone Working Reference Standard Solutions

A stock 14-hydroxycodeinone standard solution was prepared by weighing25±2 mg of 14-hydroxycodeinone reference material and transferring itinto a 250-mL volumetric flask. Approximately 100 mL of 0.85% H₃PO₄solution was added to the flask and sonicated for approximately 2minutes or until dissolved. The solution was diluted to volume with0.85% H₃PO₄ solution and mixed thoroughly. This was the stock14-hydroxycodeinone standard solution.

A working solution of 100 ppm 14-hydroxycodeinone standard solution forsystem suitability was prepared by pipetting 5.0 mL of the stock14-hydroxycodeinone standard solution into a 100-mL volumetric flask,diluting the solution to volume with water and mixing thoroughly.

A working solution of 10 ppm 14-hydroxycodeinone standard solution forsensitivity was prepared by pipetting 5.0 mL of working 100 ppm14-hydroxycodeinone standard solution into a 50-mL volumetric flask,diluting the solution to volume with water and mixing thoroughly.

A stock hydrocodone standard solution was prepared by weighing 25±2 mgof hydrocodone reference material and transferring contents into a250-mL volumetric flask. Approximately 100 mL of 0.85% H₃PO₄ solutionwas added to the flask and sonicated for approximately 2 minutes oruntil dissolved. The solution was diluted to volume with 0.85% H₃PO₄solution and mixed thoroughly.

E. Hydrocodone Working Reference Standard Solution

Stock Hydrocodone Standard Solution was prepared by weighing 25±2 mg ofHydrocodone reference material and transferring contents into a 250-mLvolumetric flask. Approximately 100 mL of 0.85% H3PO4 solution was addedto the flask and sonicated for approximately 2 minute or untildissolved. The solution was diluted to volume with 0.85% H3PO4 Solutionand mixed thoroughly.

F. Sample Solutions

A sample solution was prepared by weighing about 250 mg oxycodone APIsample into a scintillation vial. 5.0 mL of water was pipetted into thevial to dissolve the sample. The vial was tightly capped and sonicatedfor approximately 5 minutes or until the sample was dissolved. Thecontents were then shaken and mixed thoroughly.

G. Resolution Test Mixture (RTM) Solution

A solution containing two components, 14-hydroxycodeinone andhydrocodone, was prepared from the respective stock standard solutions.

The Resolution Test Mixture (RTM) was prepared by pipetting separately10.0 mL of each stock standard solution of hydrocodone above and14-hydroxycodeinone above into the same 100 mL volumetric flask anddiluted to volume with a sufficient amount of water and mixedthoroughly.

H. HPLC Conditions

The HPLC conditions were as follows:

Column: Waters, Atlantis dC18, 3 × 250 mm, 5 μm. Column temperature: 50°C. Detector wavelength: 220 nm Injection volume: 6 μl Quantitation: Peakarea of 14-hydroxycodeinone Mobile Phase: (60:40) 17 mM ammoniumcarbonate, pH 9.35-9.40:Methanol Flow rate: 0.4 mL/minute Run time: 70minutes for the samples and 40 minutes for the standard and RTMsolutions

I. Resolution Test Mixture (RTM) Test

Before performing the system suitability test, a new column wasequilibrated over night (at least 12 hours) by pumping mobile phasethrough it at 0.4 mL/min. After the new column was equilibrated, 6 μL ofRTM solution was injected into the equilibrated system to ensure thatthe two eluted component peaks did not interfere with one another. Atypical separation of the system suitability testing solution is shownin FIG. 3.

J. System Suitability Test

A system suitability test was performed by injecting the Working 100 ppm14-hydroxycodeinone standard solution into the system and by performingthe system suitability test as described in the USP <621> by making sixdifferent runs of 6 μL injections. The system suitability test resultsmet the following criteria listed in Table 1 below.

TABLE 1 Test No. System Suitability Test Specification 1 RSD of peakareas for 14- RSD ≦ 3.0% hydroxycodeinone (1) 2 RSD of retention timefor RSD ≦ 2.0% 14-hydroxycodeinone (1) 3 Column Efficiency N ≧ 2000(Theoretical Plates of 14- hydroxycodeinone) (1) 4 Resolution between14- R ≧ 1.5 hydroxycodeinone and Hydrocodone (2) 5 Signal to noise ratio(3) S/N ≧ 10 Note: (1) the working 100 ppm 14-hydroxycodeinone standardsolution for Test Nos. 1 to 3 was used. (2) the RTM for Test No. 4 wasused. (3) the working 10 ppm 14-hydroxycodeinone standard solution forTest No. 5 was used.

Before starting the experiment, 6 μL of water was injected to ensurethat there were no interfering peaks co-eluting with the peak for14-hydroxycodeinone. The following procedure was then conducted.

The working 100 ppm 14-hydroxycodeinone standard solution was injectedsix times in different runs, and the system was checked to verify thatit met the system suitability test specifications as listed for TestNos. 1, 2 and 3 in Table 1 above.

The RTM solution was injected and run once in the HPLC system to confirmthat the system met the system suitability test specification as listedfor Test No. 4 in Table 1 above.

The working 10 ppm 14-hydroxycodeinone standard solution was injectedand run once in the HPLC system to confirm that the system hadsignal-to-noise ratio S/N greater than or equal to 10, as listed in thespecification for Test No. 5 in Table 1 above.

After the system passed all of the above tests, the following HPLCprocedure was performed.

The working 100 ppm 14-hydroxycodeinone standard solution and theworking 10 ppm 14-hydroxycodeinone standard solution were each injectedseparately. Both working standard solutions were used to quantitate thesamples. The setting and integration parameters are listed in Table 2below.

TABLE 2 Integration Setting Parameters Minimum area 0 Minimum height 0Threshold 2 Peak width 90.00 Inhibit integration: 0.01 to 20 minutesEliminates solvent front

Typical HPLC chromatograms for the working 100 ppm 14-hydroxycodeinonestandard solution and the oxycodone API sample solution are shown inFIG. 4 and FIG. 5 respectively. Retention times of the14-hydroxycodeinone and other related substances are presented in Table3 below.

TABLE 3 Relative Retention Time vs. Oxycodone Peak ID (RRT)Oxycodone-N-Oxide (ONO) 0.16 Noroxycodone 0.31 Oxymorphone 0.457,8-Dihydro-8,14-Dihydroxycodeinone 0.58 (DDC) 14-Hydroxycodeine 0.7314-Hydroxycodeinone 0.79 6-α-Oxycodol 0.96 Hydrocodone 0.95 Oxycodone1.0 Thebaine 1.89The following calculations were performed using the results obtainedabove. Using Millennium®, software, the parameters were entered asfollows:In the sample set, the standard concentrations for both workingstandards (10 and 100 ppm) were calculated as follows:

${100\mspace{14mu}{PPM}\mspace{14mu}{{std}.{conc}.}} = {\frac{{W_{std}\mspace{14mu}{corrected}\mspace{14mu}{for}\mspace{11mu}{purity}}\;}{250} \times 0.05}$${10\mspace{14mu}{PPM}\mspace{14mu}{{std}.{conc}.}} = {\frac{{W_{std}\mspace{14mu}{corrected}\mspace{14mu}{for}\mspace{11mu}{purity}}\;}{250} \times 0.005}$where W_(std) is the weight of standard.The following were also entered:

Sample weight=weight of sample in mg

Dilution=5 ml (sample dilution)

Label claim=0.0001 (to convert the results in PPM.

The amount of 14-hydroxycodeinone (abbreviated as OHC) in oxycodonesample in ppm can be determined automatically from a linear calibrationcurve using the two standards (100 PPM and 10 PPM) and the equation usedin the calculation below.

${{PPM}\mspace{14mu}{of}\mspace{14mu} 14{OHC}} = {\frac{A_{sam} - Y_{intercept}}{Slope} \times \frac{D}{W_{sam}} \times 1000000}$where:A_(sam)=peak area of 14OHCY_(intercept)=Y intercept from a linear regression line using the twostandardsSlope=slope from a linear regression line using the two standardsD=5.0 (sample dilution factor)W_(sam)=sample weight in mg1000000=Convention factor to convert the result to PPM

Example 5

3.0 g of oxycodone hydrochloric salt containing 154 ppm14-hydroxycodeinone was dissolved in 20 mL water to afford a clearsolution in a 250 mL Parr reaction bottle. To the solution, 0.05 g 5%Pd/C catalyst, 50% water wet (Johnson Matthey type 87L) and 1 mL formicacid 88% were added. The mixture was placed under inert atmospherewithout hydrogen feed and then heated to 45° C.-50° C. After 2 hours ofshaking, a sample was taken to check the disappearance of14-hydroxycodeinone. The sample showed no 14-hydroxycodeinone by theHPLC method described in Example 4 above.

The solution was then suction filtered over a 0.2 micron PTFE membraneto remove the catalyst. An aliquot of 2 mL was taken out of about 18 mLfiltrate solution. To this solution, 2.0 mL isopropyl alcohol was addedto obtain a clear solution, followed by 4.0 mL of ethyl acetate. Thesolution was stirred, cooled and kept at 0-5° C. for 20 hours to affordoxycodone hydrochloride crystals. The crystalline solid was isolated bysuction filtration. The wet solid was dried in an oven at 50° C. and 10mmHg pressure. The dried solid weighed 0.12 g.

Analysis using the HPLC method in Example 4 above indicated that about11 ppm 14-hydroxycodeinone were present in the oxycodone hydrochloridesalt composition. In another aliquot of 2 mL of the filtrate solution,16-18 mL of isopropyl alcohol was added to the concentrated oxycodonehydrochloride solution followed by crystallization and drying. Theprocedure afforded oxycodone hydrochloride salt containing about 6.8 ppm14-hydroxycodeinone.

Example 6

Analysis of Sample to Determine 14-Hydroxycodeinone and Codeinone

The products of Examples 1-3 were analyzed by the following alternativemethod to determine the amount of codeinone and 14-hydroxycodeinonepresent. This method uses a Waters Symmetry C₁₈ column maintained at 40°C. with isocratic elution using a mobile phase of sodium phosphatebuffer, sodium dodecyl sulfate (SDS), acetonitrile (ACN), and methanol(MeOH).

The reagents used were as follows:

-   -   1. Water, HPLC grade or equivalent;    -   2. Phosphoric acid, 85%, HPLC reagent grade or equivalent;    -   3. Sodium phosphate monobasic, monohydrate, Enzyme grade or        equivalent;    -   4. Sodium dodecyl sulfate (99%+), Ultrapure, Fluka or        equivalent;    -   5. Acetonitrile, HPLC grade or equivalent;    -   6. Methanol, HPLC grade or equivalent;    -   7. Sodium hydroxide, ACS reagent grade or equivalent;    -   8. Oxycodone HCl with low ABUK to be used as part of the matrix        in standard preparation;    -   9. Codeinone reference material from Rhodes Technologies or        equivalent;    -   10. 14-Hydroxycodeinone reference material from Albany Molecular        Research or equivalent

The equipment used was as follows:

A. HPLC System

For this analysis, an HPLC system with a dual wavelength detector wasused that was able to operate under isocratic conditions at a flow rateof 0.7 mL per minute with UV detection @ 220 nm, and a columntemperature of 40° C.

B. Mobile Phase Filtration System

For this analysis, an HPLC vacuum filtration apparatus with a nylonmembrane filter (0.45 μm) was used.

Solutions

i. 50% Sodium Hydroxide Solution (w/v)

-   -   50 g of sodium hydroxide pellets were weighed and transferred        into a 100-mL volumetric flask. 60-mL of water was then added        and sonicated until the pellets were completely dissolved. The        pellets were diluted to volume with water and mixed well.        (Commercially available 50% w/v NaOH solution may also be used.)        ii. Phosphoric Acid Solution I (˜8.5% H₃PO₄)

10 ml of concentrated phosphoric acid (85%) was transferred into a 100ml volumetric flask containing approximately 50 ml of water. The volumewas diluted with water and then mixed.

iii. Phosphoric Acid Solution II (˜0.85% H3PO4)

10-mL of 85% phosphoric acid was pipetted into a 1000-mL volumetricflask, diluted to volume with water and mixed well. This was the diluentfor the sample and standard preparation.

iv. Mobile Phase

3.45 g±0.1 g of sodium phosphate monobasic monohydrate monohydrate wasweighed into a 1-L flask. 1000 mL of water was added and then stirredwith a magnetic stirrer until dissolved. 5.41 g±0.1 g of sodium dodecylsulfate was added and mixed well until dissolved. This solution wasfiltered using vacuum filtration with a 0.45-μm nylon membrane filter.The pH of this solution was adjusted with 50% NaOH solution to a finalpH of 7.50±0.05.

722.5 ml of the above solution was then mixed with 157.5 mL ofacetonitrile, then 120 mL of methanol was added to the solutions andmixed well. The final pH was adjusted to 7.80±0.01 with ˜8.5% phosphoricacid solution. The mobile phase was sonicated for about 5 minutes toremove dissolved air.

i. Standard Solution Preparation Calculated Relative to Dried Samples

A. Codeinone/14-Hydroxycodeinone Stock Solution I

25±1 mg of both codeinone and 14-hydroxycodeinone reference materialswere weighed and transferred into a 100-mL volumetric flask, diluted tovolume and dissolved with ˜0.85% phosphoric acid solution II.

ii. 100 ppm Stock Standard II

1-ml of stock solution I was pipetted into a 50-ml volumetric flask,diluted to volume with ˜0.85% phosphoric acid solution II and thenmixed.

iii. 10 ppm Working Standard III

500±5 mg of Oxycodone low ABUK material was weighed into a 10-mlvolumetric flask. 1-ml of stock standard H was pipetted and diluted tovolume with ˜0.85% phosphoric acid solution II and mixed.

iv. Unspiked Oxycodone Solution

500±5 mg of Oxycodone low ABUK material was weighed into a 10-mlvolumetric flask, diluted to volume with ˜0.85% phosphoric acid solutionH and mixed. (This solution was used to calculate the residual contentof both Codeinone and 14-Hydroxycodeinone in the working standard).

E. Resolution Test Mixture (RTM)

1.0-ml of the Codeinone/14-Hydroxycodeinone stock solution I waspipetted into a 50-ml volumetric flask. Using a micropipette, 100 μl ofthe unspiked Oxycodone solution was transferred and diluted to volumewith ˜0.85% phosphoric acid solution H. The concentration of Codeinone,14-Hydroxycodeinone, and Oxycodone was approximately 100 ppm.

F. Sample Preparations

i. 50 mg/mL Oxycodone HCl Sample Solution

500±5 mg of Oxycodone HCl was weighed, in duplicate, into separate 10-mLvolumetric flasks for each of Examples 1, 2 and 3. The Oxycodone HCl wasthen diluted to volume with the ˜0.85% phosphoric acid solution H andswirled to dissolve the sample. A sufficient amount of this sample wastransferred to an HPLC vial for injection.

G. HPLC Conditions

The HPLC conditions were set as follows:

TABLE 4 HPLC Conditions Parameter Condition HPLC Column Symmetry C₁₈,3.0 × 150 mm, 3.5 μm particle size Mobile Phase 18 mM phosphate/13 mMSDS pH = 7.50:ACN:MeOH (72.25:15.75:12.0) pH = 7.80 ± 0.01 Flow Rate*0.7 mL/min Column Temperature 40° C. Detection 220 nm Injection Volume 5μL Run Time 50 minutes *Parameter may be adjusted to achieve retentiontimes.H. System Suitability

One injection (5-μL) of a blank solution (˜0.85% phosphoric acidsolution H) was made, followed by one injection of the RTM to determineif there was any interfering peaks in the blank solution. 6 injectionsof the working standard III were made. The system suitability injectionswere then tested to verify that they met the system suitability criteriaas shown in Table 2.

TABLE 5 System Suitability Criteria Acceptance Parameter CriteriaResolution between Codeinone and 14-Hydroxycodeinone NLT 8 Resolutionbetween 14-Hydroxycodeinone and Oxycodone NLT 2 Tailing factor forOxycodone 0.7-2.0 Relative retention times for Codeinone based onOxycodone Approx. 0.44 Relative retention times for 14-Hydroxycodeinonebased on Approx. 0.85 Oxycodone % RSD of 6 system suitability injectionsfor Codeinone and NMT 20% 14-HydroxycodeinoneThe expected retention times were as follows:

Expected Retention Components Times Codeinone 14 ± 2 min14-Hydroxycodeinone 27 ± 4 min Oxycodone 32 ± 6 minI. Injection Procedure

Once the column was equilibrated, the sample and standard solutions wereinjected according to the following sequence of Table 3:

TABLE 6 Blank (diluent) 1 injection Resolution solution 1 injectionWorking Standard III 6 injections for RSD, last 2 injections forcalibration Blank (diluent) 2 injections Unspiked Oxycodone solution 2injections Sample 1 Prep# 1 2 injections Working Standard III 2injections Sample 1 Prep# 2 2 injections Sample 2 Prep# 1 2 injectionsSample 2 Prep# 2 2 injections Working Standard III 2 injections Sample3, Prep# 1 2 injections Sample 3, Prep# 2 2 injections Working StandardIII 2 injections

The Codeinone and 14-Hydroxycodeinone peaks were identified using therelative retention times as discussed above.

Calculations

The responses of Codeinone and 14-Hydroxycodeinone peaks were measuredand recorded. The content of Codeinone and 14-Hydroxycodeinone wascalculated in ppm using the following equation:

${ppm} = {\frac{{Rs} \times {Wstd}}{{Rstd} \times {Ws}} \times \frac{1}{100} \times \frac{1}{50} \times \frac{1}{10} \times \frac{10}{1} \times \frac{1,000,000}{1}}$${ppm} = \frac{{Rs} \times {Wstd} \times 200}{{Rstd} \times {Ws}}$Where:

-   -   ppm=Parts per millions of codeinone or 14-Hydroxycodeinone in        Oxycodone HCl    -   Rs=Response of Codeinone or 14-Hydroxycodeinone in Sample        Solution.    -   Rstd=Response of Codeinone or 14-Hydroxycodeinone in Standard        Solution minus the response of unspiked standard    -   Wstd=Weight of Standard, corrected for purity, mg    -   Ws=Weight of Sample, mg    -   1000000=Conversion Factor for ppm        % Codeinone/14-hydroxycodeinone=ppm/10,000

The results for Example 1 utilizing the procedure of Example 6 gave aresult of <5 ppm of codeinone and 8 ppm of 14-hydroxycodeinone.

The results for Example 2 utilizing the procedure of Example 6 gave aresult of <5 ppm of codeinone and <5 ppm of 14-hydroxycodeinone.

The results for Example 3 utilizing the procedure of Example 6 gave aresult of <5 ppm of codeinone and 10 ppm of 14-hydroxycodeinone.

Many other variations of the present invention will be apparent to thoseskilled in the art and are meant to be within the scope of the claimsappended hereto.

What is claimed is:
 1. Isolated 8α,14-dihydroxy-7,8-dihydrocodeinone.